Background and Purpose The human gut bacterium Akkermansia muciniphila has been increasingly recognized for its therapeutic potential in treating metabolic disorders. However, its efficacy in preventing non-alcoholic fatty liver disease (NAFLD) and the mechanism involved in its well-known metabolic actions are unknown. The present study explored the therapeutic effect and novel mechanism of A. muciniphila in intervening NAFLD. Experimental Approach The anti-NAFLD activity of A. muciniphila was evaluated in an obese mouse model induced by high-fat and cholesterol (HFC) diets using three different interventions. The gut microbiota composition, beneficial metabolic effects in the gut-liver axis were explored. The level and beneficial metabolic effects of L-aspartate in vitro and in vivo were further determined. Key Results Mice treated with A. muciniphila efficiently reversed NAFLD in the liver, such as hepatic steatosis, inflammatory, and liver injury. These therapeutic effects persisted after long-term drug withdrawal and were slightly weakened in a germ-free mouse model. A. muciniphila treatment efficiently increased mitochondrial oxidation and bile acid metabolism in the gut-liver axis, ameliorated oxidative stress- induced cell apoptosis in the gut, leading to the reshaping of the gut microbiota composition. These metabolic improvements occurred with increased L-aspartate levels in the liver that transported from the gut. The administration of L-aspartate in vitro or in mice displayed the similar beneficial metabolic effects mentioned above. Conclusion and Implications The anti-NAFLD activity of A. muciniphila correlated with lipid oxidation and improved gut-liver interactions through regulating L-aspartate metabolism. A. muciniphila would be a potent agent for clinical intervention in NAFLD.

BACKGROUND AND PURPOSE Type II Diabetes mellitus (T2DM) is a worrying chronic metabolic disorder accompanied by multiple serious complications, makes threaten public health. In the present study, we evaluated the therapeutic effects against T2DM of the cycloastragenol (CAG), a key metabolite of astragaloside IV (AST) isolated from traditional Chinese plant Astragalus membranaceus and revealed its molecular mechanism. EXPERIMENTAL APPROACH The plasma glucose-decreasing effects of AST and CAG were monitored in KunMing mice by performing an OGTT test. Furthermore, the effect of CAG on the metabolism of Zuker diabetic fat (ZDF) rats was demonstrated after treatment for 5 weeks, as well as on diabetes-relevant clinical symptoms and glucose absorbance. The underlying molecular mechanism of the therapeutic effects of CAG was explored in both wild-type and sodium/glucose co-transporter 2 (SGLT2)-overexpressed HEK293 cells. KEY RESULTS CAG showed stronger effects in lowering plasma glucose and enhancing glucose tolerance than AST in KM mice and ZDF rats. In the ZDF rats, the potential antidiabetic properties of CAG were associated with amelioration in hyperglycemia, dyslipidemia, myocardial and kidney fibrosis. Interestingly, glucose reuptake was inhibited in the kidneys of mice treated with CAG, while urine glucose and sodium levels were elevated. The underlying mechanism might be that CAG reduced the expression of SGLT2 in the kidney and inhibited glucose transport as well. CONCLUSIONS AND IMPLICATIONS CAG can ameliorate the T2DM-related metabolic syndromes of ZDF rats by acting on the SGLT2, which provides a certain references for the application of CAG in T2DM therapy.